Endothelins are a family of 21 amino acid peptides produced by endothelial cells. There are three known isoforms of endothelin, namely endothelin-1 (ET-1), endothelin-2 (ET-2) and endothelin-3 (ET-3). Of the three known isoforms, ET-1 is the major isoform produced by the vascular endothelium and is an extremely potent vasoconstrictor, with veins being 3 to 10 times more sensitive to the effects of ET-1 than arteries.
The vasoconstricting effect of endothelin is caused by the binding of endothelin to its receptor on the vascular smooth muscle cells. Thus far, two endothelin receptors have been characterized in mammalian species, known as the ETA and ETB receptors. The ETA receptor, restricted to vascular smooth muscle, is relatively selective for ET-1 and mediates vasoconstriction. The ETB receptor, primarily located in the endothelium, mediates vasodilatation through the production of endothelium-dependent vasodilators, such as nitric oxide and prostacyclin.
A pathophysiological role for the endothelins has been postulated in a large number of human disease states.
One example of such a disease state is primary pulmonary hypertension (PPH), a rare condition of unknown etiology which affects mainly young people. PPH causes progressive shortening of breath and most of those affected are dead within 4 years of diagnosis. Patients with PPH have increased circulating endothelin levels which may be caused by increased pulmonary endothelin synthesis, and there is evidence to suggest that increased endothelin production may be directly involved in the pathogenesis of PPH (Ferro and Webb, “The Clinical Potential of Endothelin Receptor Antagonists in Cardiovascular Medicine”, Drugs 1996 January; 51(1): 12-27).
Another example of such a disease state is glaucoma, which is a group of vascular disorders characterized by degeneration of the optic nerve which carries images from the retina to the brain. The disease is associated with high intraocular pressure and impaired ocular blood flow. There are reports in the literature that ET-1 plasma levels are elevated in some forms of glaucoma (Cellini et al., “Color Doppler imaging and plasma levels of endothelin-1 in low-tension glaucoma”: Acta Ophthalmol Scand Suppl 1997; (224): 11-3). Furthermore, endothelin appears to be involved in the regulation of intraocular pressure and the modulation of ocular blood flow (Haefliger et al., “Potential role of nitric oxide and endothelin in the pathogenesis of glaucoma”, 1: Surv Ophthalmol 1999 June; 43 Supl 1: S51-8; and Sugiyama et al., “Association of endothelin-1 with normal tension glaucoma: clinical and fundamental studies” 6: Surv Ophthalmol 1995 May; 39 Suppl 1: S49-56), suggesting that endothelin may be involved in the pathogenesis of at least some forms of the disease.
Endothelin also plays a potential role in the progression of atherosclerosis (Rubanyi and Polokoff, “Endothelins: Molecular Biology, Biochemistry, Pharmacology, Physiology and Pathophysiology”, Pharmacological Reviews Vol. 46, No. 3, 1994, pp. 325-415) incorporated herein by reference. This is supported by a number of factors, including the following: plasma ET-1 levels are elevated in patients with atherosclerosis and in animal models of hypercholesterolemia; expression of the ET-1 gene is induced, synthesis and release of ET-1 peptide is increased, and binding of exogenous ET-1 is enhanced in the atheromatous vascular lesion; ET-1 production by the endothelium and macrophages is stimulated by oxidized LDL and several cytokines involved in the vascular injury process; and ET-1-induced vasoconstriction is potentiated in atherosclerosis.
Endothelin 1 (ET-1) is also a factor in promotion of angiogenesis, the development of blood vessels, a process which, properly balanced, is important in the restoration and maintenance of good health in mammals. Excess angiogenesis, however, can cause serious health problems, e.g. in recovery from cardiac incidents and in restenosis. ET-1 is known to stimulate the secretion of vascular endothelial growth factor VEGF (see for example Spinella, F. et. al., J. Biol. Chem. 2002 Aug. 2; 277 (31): 27850-5), which promotes angiogenesis. Down-regulation of ET-1 is therefore the basis of potential treatments of conditions involving excess angiogenesis.
Although the symptoms of many endothelin-related disorders can be treated, there is a lack of available treatments which address the underlying role of endothelin in these disorders. Accordingly, the need exists for an effective treatment of endothelin-related disorders.